The Holy Grail of chemotherapy is to identify drugs that can selectively recognize and destroy cancer cells while sparing normal cells. One widely-accepted biological distinction between cancer and normal cells is the number of cellular organelles called centrosomes. While normal cells stringently possess two centrosomes, cancer cells have far too many centrosomes. Centrosomes exquisitely orchestrate the assembly of an elegant bipolar cell division apparatus, called the mitotic spindle, for faithful segregation of genetic material between two daughter cells. Although extra centrosomes offer a growth advantage to cancer cells, these overabundant organelles might lead to multipolar spindle formation that is detrimental to cell survival. To combat this potential catastrophe, cancer cells have evolved sophisticated and clever mechanisms to cluster excess centrosomes and assemble a pseudo-bipolar mitotic spindle that is conducive to cell division, thereby allowing cancer cells to survive, thrive and be merry. We rationalize that depleting breast cancer cells of their centrosome-clustering arsenal will result in cells with highly aberrant multipolar spindle, which will serve as a point of no return and result in a chaotic mitosis that consigns cells to their demise. Our laboratory has identified that a recently discovered centrosome clustering protein, HSET, is selectively upregulated in human breast cancer tissues compared to normal breast epithelia. Interestingly, the enhanced expression of HSET directly correlates with increasing tumor grade and disease progression. Most currently-available anticancer drugs target cellular components with vital functions in normal cells. HSET is non-essential in normal cells but is required for cancer cell survival. The differential dependence of normal versus cancer cells on HSET for viability makes HSET an invaluable cancer-cell selective chemotherapeutic target. We hypothesize that HSET is a novel oncogene that can serve as a clinical biomarker for breast cancer prognosis and a cancer-cell selective therapeutic target for the design and preclinical development of small-molecule HSET inhibitors for non-toxic breast cancer therapy. Thus our objectives are a) to establish the oncogenic role of HSET in breast cancer development and progression, b) evaluate whether HSET can serve as a clinical biomarker for breast cancer detection and prognosis, and c) preclinically develop a novel class of HSET inhibitors that robustly decluster centrosomes. Our proposal has strong clinical and translational relevance. We anticipate that the successful completion of this project will serve to a) yield a new clinical biomarker for breast cancer detection and prognosis, which can potentially impact patient stratification for customized therapy, b) aid the development of a novel class of HSET inhibitors that can selectively target breast cancer cells while sparing normal cells, thus improving breast cancer patients' quality of life, and c) enhance the knowledge base of breast cancer biology to uncover novel targets based upon the centrosome, a key orchestrator of cell division. PUBLIC HEALTH RELEVANCE: Our project is a promising step forward in the application of cell biology to human disease since it has strong clinical and translational relevance. It seeks to establish a centrosome-clustering protein, HSET, as a novel oncogene that may potentially play a key role in breast cancer development and progression. We would thus be adding a new and important element to the molecular profile/signature of breast cancer. HSET might be a novel clinical biomarker for breast cancer detection and prognosis that could impact breast cancer screening, evaluation of response to treatment, and patient stratification for customized therapy to improve patient outcomes. Importantly, our molecule under study, HSET, is non-essential in normal cells but is required for cancer cell survival. This differential dependence makes HSET an invaluable cancer-cell selective therapeutic target, allowing us to design selective inhibitors directed against it. Lastly, development of a novel class of HSET inhibitors that can selectively combat breast cancer while sparing normal cells would impact disease- free survival without compromising the quality of life of breast cancer patients.